1. Field of the Invention
The present invention relates to a process for producing a cyclic peptide, which is useful as an antifungal drug, through total synthesis. Further, it relates to a novel cyclic peptide produced by the process.
2. Description of Related Art
There have been known more than 20 aureobasidins in addition to aureobasidin A (refer to Japanese Patent Laid-Open No. 138296/1990, No. 22995/1991, No. 44398/1991, No. 220199/1991 and No. 79078/1992). Each of these aureobasidins is a cyclic peptide composed of nine amino acids (or hydroxy acids), and has been produced as a fermentation product obtained by microbiological methods with the use of fungi, for example, Aureobasidium pullulans R106. Aureobasidins are highly useful as an antifungal drug having low toxicity and potent fungicidal activity on various pathogenic fungi. Aureobasidin A (SEQ ID No:1) has a chemical structure represented by the following formula (IV), which was determined with the use of physical and chemical analytical techniques (refer to J. Antibiotics, 44 (9), 925-933 (1991). ##STR2## wherein D-Hmp represents 2(R)-hydroxy-3(R)-methylpentanoate residue.
Each of these compounds is produced either by a microbiological method or a semisynthetic method and, therefore, chemical modifications of these compounds are restricted. As a result, the development of aureobasidins are seriously restricted and, therefore, it has been urgently desired to complete a method for the total synthesis of aureobasidins. In the microbiological method, an aureobasidin is obtained together with well over ten congeners having similar structures. Thus it is necessary to separate a target aureobasidin therefrom. However, the separation is highly difficult and requires much labor, including the use of high performance liquid chromatography. Thus it has been urgently desired to establish a method for selectively synthesizing the target aureobasidin.
The first reason why the total synthesis of an aureobasidin has been impossible in the past resides in the complicated N-methylated structure involved in the aureobasidin molecule. The second reason resides in the final cyclization step. Regarding the first problem, there have been reported a number of coupling reactions for synthesizing peptides. However, most of coupling reactions of an N-methylated amino acid and another amino acid result in only a poor yield with frequent isomerization, which requires complicated separation procedures to isolate an target peptide. Therefore, the synthesis of a peptide containing N-methylated amino acids is almost impossible in practice. Among cyclic peptides containing N-methylated amino acids, a total synthesis of cyclosporin A consisting of 11 amino acids five of which are N-methylated has succeeded (refer to Japanese Patent Publication No. 23560/1991). However every aureobasidin is entirely different from cyclosporin A in the amino acid composition. Namely, no amino acid but MeVal is common to both compounds. Further, the aureobasidin differs from cyclosporin A in the points that the aureobasidin is a cyclic depsipeptide having an ester bond in the molecule, and that some aureobasidins with high antifungal activity, such as aureobasidin A, contain .beta.HOMeVal, which is a scarce amino acid in nature. Thus, as a matter of course, the method for synthesizing an aureobasidin differs from that for cyclosporin A in various points. Now the second problem as described above will be discussed. Supposing that a linear peptide of the aureobasidin might be obtained, it is unclear whether a cyclization would proceed so as to give the target aureobasidin. Even if cyclization occurs, there is a high possibility that a mixture of complicated compounds would result from isomerization. It is, therefore, impossible to suppose which amino acids (or a hydroxy acid) should be coupled by cyclization, namely which linear peptide should be synthesized and whether the linear peptide can be cyclized so as to give the target stereochemically pure aureobasidin or not. Although we actually attempted to synthesize aureobasidin A by cyclization reaction via an ester bond of the hydroxypeptide of the formula (V) (SEQ ID No:2, refer to Japanese Patent Laid-Open No. 41093/1991), which seemingly suffers from less isomerization, by various known methods, the target aureobasidin A could not be synthesized. EQU D-Hmp.fwdarw.MeVal.fwdarw.Phe.fwdarw.MePhe.fwdarw.Pro.fwdarw.aIle.fwdarw.Me Val.fwdarw.Leu.fwdarw..beta.HOMeVal-OH (V)
In the total synthesis of cyclosporin A described in the Japanese Patent Publication No. 23560/1991 cited above, they succeeded in cyclization for the first time when a certain linear undecapeptide was created and employed. More specifically, in the case of a cyclic peptide having a complicated stereochemical structure such as cyclosporin A, its linear peptide per se to be used as a raw material has a specific stereochemical structure by virtue of its peptide sequence. Therefore, when a linear peptide except for the above mentioned linear undecapeptide is used, there is no possibility that such a linear compound is folded into a necessary form so as to give a circular configuration wherein both ends are bonded to each other. In other methods for synthesizing various cyclosporin A derivatives (refer to British Patent Laid-Open No. 2212499A, U.S. Pat. No. 4,798,823 and British Patent Laid-Open No. 2207678A), in fact, their linear undecapeptides has been synthesized to cyclize at the same position as the one indicated in the above mentioned Japanese patent and cyclized.